Date of Award

5-2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Cancer and Developmental Biology

Research Advisor

Suzanne J. Baker, Ph.D.

Committee

Michael A. Dyer, Ph.D. James I. Morgan, Ph.D. Lawrence M. Pfeffer, Ph.D. Gerard P. Zambetti, Ph.D.

Keywords

PTEN, subventricular zone, cerebellum, medulloblastoma

Abstract

PTEN (Phosphatase and Tensin homolog deleted on chromosome 10) is a tumor suppressor gene that is commonly mutated in multiple types of human cancers including endometrial, prostate, breast cancers and glioblastoma multiforme (GBM). PTEN functions as a phospholipid phosphatase antagonizing phosphorylation by phosphatidylinositol‑3‑OH kinases (PI3Ks) and thus serves as a major negative regulator of the PI3K pathway. Homozygous Pten knock-out mice die during embryogenesis. Conditional Pten knock-out in the nervous system showed that Pten negatively regulates self-renewal and proliferation of neural stem cells, negatively controls neuronal size, is required for proper neuronal positioning and is involved in the development and maintenance of normal function for oligodendrocytes and astrocytes.

Neuronal precursors (neuroblasts) are generated every day throughout life in the subventricular zone (SVZ) and migrate through the rostral migratory stream (RMS) to the olfactory bulb where they differentiate into mature interneurons. The signaling pathways instructing when and where these tangentially migrating neuroblasts stop are largely unknown. In this study, we found that the PI3K‑Akt‑mTorc1 pathway is selectively inactivated in the migrating neuroblasts in the wild-type subventricular zone and rostral migratory stream and activated when they reach the olfactory bulb. Postnatal deletion of Pten in the SVZ resulted in aberrant activation of the PI3K‑Akt‑mTorc1 pathway and enlarged SVZ and RMS. This was caused by premature termination of migration and differentiation of neuroblasts, and could be rescued by inhibition of mTorc1. Although this is consistent with previous studies in lower organisms showing that Pten was required for directional migration, live imaging of acute brain slices showed that the migrating Pten-deficient neuroblasts were not defective in speed and showed appropriate directional movement. Therefore, the apparent "migration defect" in Pten-deficient neurons was secondary to ectopic differentiation rather than an intrinsic defect in directional migration.

Inactivation of Pten in the neural stem/progenitor cells at birth also revealed a novel perivascular proliferative niche in the cerebellum without full-blown tumor formation. Co-deletion of Pten and Trp53, two commonly mutated tumor suppressor genes in human brain tumors, could synergize in generating high-penetrant medulloblastoma with a growth pattern centering around blood vessels and extensive neuronal differentiation. The Pten and Trp53 double knock-out medulloblastomas spontaneously lost chromosome 7, 13 and 16 and had mutations in the gene Ptch1. Therefore the PI3K and Shh pathways cooperate in generating medulloblastomas.

Our results show Pten is required for appropriate positioning of neuronal differentiation and preventing ectopic neural stem/progenitor proliferation and medulloblastoma genesis.

DOI

10.21007/etd.cghs.2011.0383

Comments

Two year embargo expired May 2013

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